Choi Hyun-Gyu, Jeon Ji-Young, Im Yong-Jin, Kim Yunjeong, Song Eun-Kee, Seo Young-Hwan, Cho Seok-Je, Kim Min-Gul
Clinical Trial Center and Biomedical Research Institute, Chonbuk National University Hospital, 20, Geonji-ro, Deokjin-Gu, Jeonju-si, Jeollabuk-do, 561-712, Republic of Korea.
Clin Drug Investig. 2015 Jan;35(1):31-43. doi: 10.1007/s40261-014-0248-4.
Erlotinib is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor that acts on the epidermal growth factor receptor and inhibits cell proliferation, growth, migration, invasion and survival. This study was performed for the subsequent marketing of a test erlotinib formulation in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy adult volunteers.
A total of 46 healthy male subjects were enrolled in a single-dose, randomized, open-label, two-period, two-sequence, crossover, bioequivalence study. During each treatment period, subjects received 150 mg of erlotinib in either the test or reference formulation. There was a 2-week washout period between each period. Blood samples were obtained 15 times during each period, before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72 and 96 h after oral administration. Plasma concentrations of erlotinib were determined using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (C(max)), area under the plasma concentration-time curve to the last sampling time (AUC(t)), AUC from time zero to infinity (AUC(∞)), and time to reach C(max) (t(max)), were measured, and all treatment-emergent adverse events and their relationships with the study medications were recorded throughout the study. An additional analysis was performed to characterize the association between the cytochrome P450 (CYP) 1A1, CYP1A2 and CYP3A4 genotypes and the erlotinib pharmacokinetic parameters.
A total of 41 subjects completed the study. There were no significant differences in the prevalence of adverse events between the two formulations, and there were no serious or unexpected adverse events during the study. Both formulations had very similar C(max), AUC, terminal half-life (t ½) and t(max) values. The 90% confidence intervals of the geometric least-squares mean ratios of the test to reference formulation were 1.09 (0.98-1.22) for C(max) and 1.10 (1.01-1.21) for AUCt. Statistical significance was observed between the CYP1A2*1M genotype and the erlotinib pharmacokinetic parameter, particularly C(max) (p = 0.015).
This study suggests that the test and reference formulations of 150 mg erlotinib have similar pharmacokinetic characteristics. Both had no major safety issues and were well-tolerated. The test formulation met the regulatory criteria for assuming bioequivalence to the reference formulation for both AUCt and C max. The additional genetic analysis demonstrated that the major metabolic enzymes of erlotinib did not significantly affect erlotinib metabolism, with the exception of CYP1A2*1M.
厄洛替尼是一种用于治疗非小细胞肺癌、胰腺癌及其他几种癌症的药物。它是一种可逆的酪氨酸激酶抑制剂，作用于表皮生长因子受体，抑制细胞增殖、生长、迁移、侵袭和存活。本研究旨在使一种厄洛替尼试验制剂在韩国上市。我们评估了该试验制剂与参比制剂在健康成年志愿者中的相对生物利用度和耐受性。
46名健康男性受试者参与了一项单剂量、随机、开放标签、两周期、两序列、交叉生物等效性研究。在每个治疗周期中，受试者接受150mg厄洛替尼的试验制剂或参比制剂。每个周期之间有2周的洗脱期。在每个周期内给药前及给药后0.5、1、1.5、2、2.5、3、4、6、8、12、24、48、72和96小时采集15次血样。采用液相色谱 - 串联质谱法测定血浆中厄洛替尼的浓度。测量药代动力学参数，包括最大血浆浓度（C(max)）、至最后一次采样时间的血浆浓度 - 时间曲线下面积（AUC(t)）、从零至无穷大的AUC（AUC(∞)）以及达到C(max)的时间（t(max)），并在整个研究过程中记录所有治疗期间出现的不良事件及其与研究药物的关系。进行了一项额外分析，以表征细胞色素P450（CYP）1A1、CYP1A2和CYP3A4基因型与厄洛替尼药代动力学参数之间的关联。
共有41名受试者完成了研究。两种制剂不良事件的发生率无显著差异，研究期间未出现严重或意外的不良事件。两种制剂的C(max)、AUC、末端半衰期（t½）和t(max)值非常相似。试验制剂与参比制剂几何最小二乘均值比的90%置信区间，C(max)为1.09（0.98 - 1.22），AUCt为1.10（1.01 - 1.21）。观察到CYP1A2*1M基因型与厄洛替尼药代动力学参数之间存在统计学显著性差异，尤其是C(max)（p = 0.015）。
本研究表明，150mg厄洛替尼的试验制剂和参比制剂具有相似的药代动力学特征。两者均无重大安全问题，耐受性良好。试验制剂在AUCt和C max方面符合假定与参比制剂生物等效的监管标准。额外的基因分析表明，除CYP1A2*1M外，厄洛替尼的主要代谢酶对其代谢无显著影响。
